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      Chimeric Antigen Receptors Combining 4-1BB and CD28 Signaling Domains Augment PI3kinase/AKT/Bcl-XL Activation and CD8+ T Cell–mediated Tumor Eradication

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      Molecular Therapy
      Springer Nature

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          Abstract

          To enhance the strength of activation afforded by tumor antigen-specific receptors, we investigated the effect of adding combined CD28 and 4-1BB costimulatory signaling domains to a chimeric antigen receptor (CAR) specific for prostate-specific membrane antigen (PSMA). Having transferred receptors encompassing the CD28, 4-1BB, and/or CD3zeta cytoplasmic domains in primary human CD8(+) T cells, we find that the P28BBz receptor, which includes all three signaling domains, is superior to receptors that only include one or two of these domains in promoting cytokine release, in vivo T-cell survival and tumor elimination following intravenous T-cell administration to tumor-bearing severe combined immunodeficient (SCID)/beige mice. Upon in vitro exposure to PSMA, the P28BBZ receptor-induced the strongest PI(3)Kinase/Akt activation and Bcl-X(L) expression, and the least apoptosis in transduced peripheral blood CD8(+) T cells. These findings further support the concept of integrating optimized costimulatory properties into recombinant antigen receptors to augment the survival and function of genetically targeted T cells within the tumor microenvironment.

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          Author and article information

          Journal
          Molecular Therapy
          Molecular Therapy
          Springer Nature
          15250016
          February 2010
          February 2010
          : 18
          : 2
          : 413-420
          Article
          10.1038/mt.2009.210
          2839303
          19773745
          cf513d23-383d-4b03-ad29-7109dacc10e5
          © 2010

          https://www.elsevier.com/tdm/userlicense/1.0/

          http://creativecommons.org/licenses/by-nc-nd/4.0/


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